title: Convergent patterns of association between phenylalanine hydroxylase variants and schizophrenia in four independent samples.
abstract: Recessive mutations in the phenylalanine hydroxylase (PAH) gene predispose to phenylketonuria (PKU) in conjunction with dietary exposure to phenylalanine. Previous studies have suggested PAH variations could confer risk for schizophrenia, but comprehensive follow-up has not been reported. We analyzed 15 common PAH "tag" SNPs and three exonic variations that are rare in Caucasians but common in African-Americans among four independent samples (total n = 5,414). The samples included two US Caucasian cohorts (260 trios, 230 independent cases, 474 controls), Bulgarian families (659 trios), and an African-American sample (464 families, 401 controls). Analyses of both US Caucasian samples revealed associations with five SNPs; most notably the common allele (G) of rs1522305 from case-control analyses (z = 2.99, P = 0.006). This SNP was independently replicated in the Bulgarian cohort (z = 2.39, P = 0.015). A non-significant trend was also observed among African-American families (z = 1.39, P = 0.165), and combined analyses of all four samples were significant (rs1522305: chi(2) = 23.28, 8 d.f., P = 0.003). Results for rs1522305 met our a priori criteria for statistical significance, namely an association that was robust to multiple testing correction in one sample, a replicated risk allele in multiple samples, and combined analyses that were nominally significant. Case-control results in African-Americans detected an association with L321L (P = 0.047, OR = 1.46). Our analyses suggest several associations at PAH, with consistent evidence for rs1522305. Further analyses, including additional variations and environmental influences such as phenylalanine exposure are warranted.
authors.affiliation: Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Talkowski
authors.forename: Lora
authors.initials: L
authors.lastname: McClain
authors.forename: Trina
authors.initials: T
authors.lastname: Allen
authors.forename: L Dianne
authors.initials: LD
authors.lastname: Bradford
authors.forename: Monica
authors.initials: M
authors.lastname: Calkins
authors.forename: Neil
authors.initials: N
authors.lastname: Edwards
authors.forename: Lyudmila
authors.initials: L
authors.lastname: Georgieva
authors.forename: Rodney
authors.initials: R
authors.lastname: Go
authors.forename: Ruben
authors.initials: R
authors.lastname: Gur
authors.forename: Raquel
authors.initials: R
authors.lastname: Gur
authors.forename: George
authors.initials: G
authors.lastname: Kirov
authors.forename: Kodavali
authors.initials: K
authors.lastname: Chowdari
authors.forename: Joseph
authors.initials: J
authors.lastname: Kwentus
authors.forename: Paul
authors.initials: P
authors.lastname: Lyons
authors.forename: Hader
authors.initials: H
authors.lastname: Mansour
authors.forename: Joseph
authors.initials: J
authors.lastname: McEvoy
authors.forename: Michael C
authors.initials: MC
authors.lastname: O'Donovan
authors.forename: Judith
authors.initials: J
authors.lastname: O'Jile
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Owen
authors.forename: Alberto
authors.initials: A
authors.lastname: Santos
authors.forename: Robert
authors.initials: R
authors.lastname: Savage
authors.forename: Draga
authors.initials: D
authors.lastname: Toncheva
authors.forename: Gerard
authors.initials: G
authors.lastname: Vockley
authors.forename: Joel
authors.initials: J
authors.lastname: Wood
authors.forename: Bernie
authors.initials: B
authors.lastname: Devlin
authors.forename: Vishwajit L
authors.initials: VL
authors.lastname: Nimgaonkar
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics; D010651:Phenylalanine Hydroxylase / Q000235:genetics*; D010661:Phenylketonurias / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics*
chemical_list: D010651:Phenylalanine Hydroxylase